The candidate, Lisa A. Lesniewski Ph.D., is a physiologist in the Department of Integrative Physiology at the University of Colorado at Boulder. Dr. Lesniewski's research focuses on the mechanisms mediating vascular and metabolic dysfunction with aging and how habitual aerobic exercise can preserve physiological function with aging. Her immediate goal is to acquire new research and professional skills that will help her to achieve her long-term career goal of developing a successful independent, extramurally-funded research program on the prevention and treatment of vascular and metabolic aging. The proposed KO1 award will provide Dr. Lesniewski the necessary support to achieve this goal. CAREER DEVELOPMENT PLAN. Dr. Lesniewski's research career development training activities will consist of: 1) acquiring new research skills associated with and complementary to the proposed research plan;and 2) structured activities including formal course-work, attendance and presentations at weekly journal clubs, university seminar series and scientific meetings, and regular interactions with her mentoring team. ENVIRONMENT. The environment for Dr. Lesniewski's training should be outstanding. The sponsor, Dr. Douglas Seals, is a well-established extramurally-funded scientist with a strong record of successful mentoring in biomedical aging research. He is complemented by a group of consulting mentors that consist of internationally- recognized investigators, each providing specific expertise in a key area of Dr. Lesniewski's research project and overall training plan. RESEARCH. The aims of the research project are to establish if aging increases susceptibility to the deleterious effects of a high fat, or Western diet (WD) by exacerbating chronic low grade inflammation and to determine if habitual exercise can prevent the deleterious effects of WD on vascular and metabolic function by reducing inflammation. The proposed research will use an "integrative" (system to gene) approach in young, middle-aged, and older mice to identify the cellular and molecular mechanisms by which WD causes inflammation-associated endothelial and metabolic dysfunction with aging and regular exercise exerts protective effects. The results should provide clinically important information regarding: 1) the influence of aging in altering vulnerability to a commonly encountered factor, WD and 2) the mechanisms by which WD causes and habitual exercise prevents these deleterious effects. PUBLIC HEALTH RELEVANCE: Advancing age and consumption of a WD are associated with vascular and metabolic dysfunction and disease. However, it is unknown if the adverse effects of WD become greater with aging, the mechanisms by which this occurs, and if these effects can be prevented by habitual aerobic exercise.